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J Clin Invest. 2012 Dec;122(12):4490-504. doi: 10.1172/JCI65102. Epub 2012 Nov 19.

C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia.

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1
Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.

Erratum in

  • J Clin Invest. 2013 Jan 2;123(1):526. DiRuscio, Annalisa [corrected to Di Ruscio, Annalisa].

Abstract

C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.

PMID:
23160200
PMCID:
PMC3533560
DOI:
10.1172/JCI65102
[Indexed for MEDLINE]
Free PMC Article
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